1. Field of the Invention
The present invention relates to novel nucleoside-phospholipid conjugates and salts thereof. More particularly, the present invention relates to a nucleoside-phospholipid conjugate of the formula ##STR2## wherein R.sub.1 is C.sub.14-24 aliphatic acyl or C.sub.1-24 aliphatic alkyl, R.sub.2 is C.sub.2-10 aliphatic acyl or C.sub.1-24 aliphatic alkyl, and N.sub.s is a nucleoside residue, and salts thereof.
2. Description of the Prior Art
Nucleoside antitumor agents have been widely used as effective chemotherapeutics for neoplastic cells. In their application as antitumor-chemotherapeutics, however, several problems have arisen. For example, in the mechanism for the activity of nucleoside anti-neoplastic agents, in vivo phosphorylation of the hydroxyl group at the nucleoside 5' position is essential for antitumor activity; the agent is decomposed to an inactive substance by inactivation reactions such as phosphorolysis and deamination; the resistance of tumor cells to antitumor agents increases; and the agent is sometimes toxic to normal mitotic cells. Many kinds of nucleoside derivatives have been synthesized to overcome the disadvantages of known nucleoside antitumor agents.
CDP-diacylglycerol is known to have an important role as an intermediate in the biosynthesis of glycerophospholipid in vivo. Its analogue, arabinosylcytosine-phospolipid conjugate, which has antitumor activity, has been chemically synthesized [Biochim. Biophys. Acta, 619, 619-631 (1980), J. Med. Chem., 1982, 25, 1322-1329].
5-fluoro-2-deoxyuridine-phospholipid conjugate (Japan Unexam. Pat. Publ. No. 61-91195, No. 61-152694) and a process for manufacturing heterocyclic phospholipid conjugate by phospholipase DM (ibid. No. 61-88890) have also been reported.
This prior art has a number of disadvantages. Synthesis of these known compounds is a complicated multistep process with quite low overall yield. Moreover, these synthetic compounds are only sparingly soluble in aqueous media, and are thus difficult to use as injectable preparations.
Furthermore, previously reported nucleoside-phospholipid conjugates comprise an ester linkage of glyceride and a hydrophobic fatty acid in a phospholipid backbone, and hence are easily decomposed by phospholipase A.sub.1 or phospholipase A.sub.2 in vivo. Stability of these compounds is also unsatisfactory.